7-Bromo-4-Chloro-3-Nitroquinoline: Properties & Applications

7-Bromo-4-chloro-3-nitroquinoline is a multifunctionally activated quinoline building block bearing halogen substituents and a nitro group that make it a versatile electrophilic intermediate for medicinal chemistry and heterocyclic synthesis.

Chemical Name

7-Bromo-4-chloro-3-nitroquinoline

SKU

B186251

Molecular Formula

C9H4BrClN2O2

Molecular Weight

287.50 g/mol

Key Functional Groups

Bromo (C-7), Chloro (C-4), Nitro (C-3) on quinoline ring

Primary Use

Electrophilic building block for nucleophilic aromatic substitution and cross-coupling reactions

Storage Recommendation

Store in a cool, dry place away from light and moisture

Chemical Structure and Physicochemical Properties

7-Bromo-4-chloro-3-nitroquinoline (molecular formula C₉H₄BrClN₂O₂; MW ≈ 287.50 g/mol) is a trisubstituted quinoline in which three distinct electron-withdrawing or halogen substituents are positioned at the 3-, 4-, and 7-positions of the bicyclic ring system. The nitro group at C-3 and the chloro substituent at C-4 together create a strongly electron-deficient aromatic ring, rendering the C-4 position exceptionally susceptible to nucleophilic aromatic substitution (S_NAr). The bromo substituent at C-7 provides an orthogonal handle for transition-metal-catalyzed cross-coupling reactions such as Suzuki–Miyaura, Buchwald–Hartwig, and Sonogashira protocols. As a solid compound, it is expected to possess moderate lipophilicity consistent with other polyhalogenated nitroquinolines, though precise melting point and logP data should be confirmed from the supplier certificate of analysis.

Synthesis Utility and Reaction Pathways

The compound's three reactive sites enable sequential or orthogonal functionalization strategies that are highly valued in medicinal chemistry programs and library synthesis. The C-4 chloro group is the most electrophilically activated position and undergoes facile S_NAr reactions with amines, alkoxides, and thiols under mild to moderate conditions. This selectivity allows introduction of diverse heteroatom-containing fragments, forming 4-amino-, 4-alkoxy-, or 4-thio-substituted quinoline scaffolds that serve as privileged structures in kinase inhibitor and antimicrobial research.

The C-7 bromo substituent is well-suited for palladium- or nickel-catalyzed cross-coupling, enabling introduction of aryl, heteroaryl, alkenyl, or alkynyl groups. The C-3 nitro group can subsequently be reduced to a primary amine using standard reagents such as iron/acetic acid, tin(II) chloride, or catalytic hydrogenation, providing an additional amine handle for further acylation, cyclization, or diazotization. This multi-step diversification from a single starting material makes 7-bromo-4-chloro-3-nitroquinoline an efficient platform for generating structurally complex quinoline libraries.

Research and Medicinal Chemistry Applications

Quinoline scaffolds bearing halogen and nitro substituents are widely recognized as privileged structural motifs in drug discovery. Derivatives accessible from 7-bromo-4-chloro-3-nitroquinoline have potential relevance across several therapeutic areas. The 4-anilinoquinoline and 4-aminoquinoline frameworks derived via S_NAr at C-4 are associated with kinase inhibitory activity, particularly against epidermal growth factor receptor (EGFR) and related targets. The C-7 bromo position allows introduction of solubilizing or pharmacophoric aryl groups through cross-coupling to modulate potency and selectivity. Reduction of the nitro group to an amine opens pathways to fused heterocyclic systems such as quinoline-3-carboxamides or imidazo[1,2-a]quinolines through intramolecular cyclization. Beyond oncology, halogenated quinolines have reported activity in antimalarial, antibacterial, and antifungal contexts, supporting use of this building block in broad-spectrum biological screening programs.

Researchers in chemical biology may also employ this compound as an electrophilic probe or as a precursor to fluorescent quinoline dyes and metal-chelating ligands, given the capacity of functionalized quinolines to coordinate transition metals.

Handling, Safety, and Storage

As a compound bearing both halogen substituents and a nitro group, 7-bromo-4-chloro-3-nitroquinoline should be handled with standard laboratory precautions appropriate for reactive aromatic intermediates. Researchers are advised to consult the Safety Data Sheet (SDS) provided by Aladdin Scientific before use. General recommended practices include working in a well-ventilated fume hood, using appropriate personal protective equipment (gloves, lab coat, and eye protection), and avoiding inhalation of dust or vapors.

The compound should be stored in a tightly sealed container in a cool, dry location away from direct light and sources of ignition. Incompatibility with strong reducing agents and strong bases should be considered when planning reactions or waste disposal. Waste containing this compound should be disposed of in accordance with applicable local and institutional regulations for halogenated organic waste. Specific hazard classifications, GHS pictograms, and first-aid measures are detailed in the product SDS available from Aladdin Scientific.

Frequently asked questions

What makes the C-4 position of 7-bromo-4-chloro-3-nitroquinoline more reactive than C-7 toward nucleophiles?

The C-4 chloro group benefits from synergistic electron withdrawal by both the ring nitrogen (adjacent at N-1) and the C-3 nitro group, strongly activating C-4 toward nucleophilic aromatic substitution. The C-7 bromo group does not experience this dual activation and is instead reserved as a handle for palladium-catalyzed cross-coupling reactions.

How can the nitro group in 7-bromo-4-chloro-3-nitroquinoline be selectively reduced without affecting the halogens?

Mild reduction conditions such as iron powder with acetic acid or tin(II) chloride in ethanol are commonly used to reduce aromatic nitro groups to amines while largely preserving aryl C–Br and C–Cl bonds. Catalytic hydrogenation should be used with caution, as palladium catalysts may promote hydrodehalogenation under forcing conditions. Reaction optimization and careful monitoring are recommended.

Is 7-bromo-4-chloro-3-nitroquinoline suitable for Suzuki–Miyaura cross-coupling at C-7?

Yes. The C-7 aryl bromide is a competent partner in Suzuki–Miyaura cross-coupling with arylboronic acids under standard palladium catalysis (e.g., Pd(PPh3)4 or Pd(dppf)Cl2) and base conditions. The electron-deficient quinoline ring can facilitate oxidative addition to palladium. Selective coupling at C-7 can be achieved without disturbing the C-4 chloro group, which is less reactive toward oxidative addition under typical Suzuki conditions.

What solvents are typically used for SNAr reactions at the C-4 position?

Polar aprotic solvents such as dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), and acetonitrile are most commonly employed for SΝAr reactions at activated quinoline C-4 positions, as they stabilize the anionic Meisenheimer complex intermediate and improve nucleophile reactivity. Reaction temperature and base selection should be optimized according to the specific nucleophile used.

References

1. Comprehensive Medicinal Chemistry II, Volume 4: Computer-Assisted Drug Design. Elsevier, 2007. (Quinoline scaffold discussion in kinase inhibitor design.)
2. March, J. Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4th ed. Wiley-Interscience, 1992. (Nucleophilic aromatic substitution mechanisms.)
3. Miyaura, N.; Suzuki, A. Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds. Chemical Reviews, 1995, 95(7), 2457–2483. doi:10.1021/cr00039a007
4. Aladdin Scientific Product Page. 7-Bromo-4-chloro-3-nitroquinoline, SKU B186251. Aladdin Scientific, accessed 2024.

Products are supplied for research and development use only. Not for use in humans, animals, diagnosis, or therapy.